9-substituted minocycline compounds

ABSTRACT

The present invention pertains, at least in part, to novel 9-substituted minocycline compounds. These minocycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms, as well as other known applications for minocycline and tetracycline compounds in general, such as blocking tetracycline efflux and modulation of gene expression.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional PatentApplication Serial No. 60/275,621, entitled “9-Substituted MinocyclineCompounds,” filed on Mar. 13, 2001, and U.S. Provisional PatentApplication Serial No. 60/216,580, entitled “9-Substituted MinocyclineCompounds,” filed on Jul. 7, 2000; both of these applications are herebyincorporated herein by reference. This application is related to U.S.Provisional Application No. 60/154,701, filed on Sep. 14, 1999; No.60/193,972, filed on Mar. 31, 2000; No. 60/193,879, filed on Mar. 31,2000; No. 60/204,158, filed on May 15, 2000; No. 60/212,030, filed Jun.16, 2000; and No. 60/212,471, filed Jun. 16, 2000, the entire contentsof each of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] The development of the tetracycline antibiotics was the directresult of a systematic screening of soil specimens collected from manyparts of the world for evidence of microorganisms capable of producingbacteriocidal and/or bacteriostatic compositions. The first of thesenovel compounds was introduced in 1948 under the name chlortetracycline.Two years later, oxytetracycline became available. The elucidation ofthe chemical structure of these compounds confirmed their similarity andfurnished the analytical basis for the production of a third member ofthis group in 1952, tetracycline. A new family of tetracyclinecompounds, without the ring-attached methyl group present in earliertetracyclines, was prepared in 1957 and became publicly available in1967; and minocycline was in use by 1972.

[0003] Recently, research efforts have focused on developing newtetracycline antibiotic compositions effective under varying therapeuticconditions and routes of administration. New tetracycline analogues havealso been investigated which may prove to be equal to or more effectivethan the originally introduced tetracycline compounds. Examples includeU.S. Patent Nos. 2,980,584; 2,990,331; 3,062,717; 3,165,531; 3,454,697;3,557,280; 3,674,859; 3,957,980; 4,018,889; 4,024,272; and 4,126,680.These patents are representative of the range of pharmaceutically activetetracycline and tetracycline analogue compositions.

[0004] Historically, soon after their initial development andintroduction, the tetracyclines were found to be highly effectivepharmacologically against rickettsiae; a number of gram-positive andgram-negative bacteria; and the agents responsible for lymphogranulomavenereum, inclusion conjunctivitis, and psittacosis. Hence,tetracyclines became known as “broad spectrum” antibiotics. With thesubsequent establishment of their in vitro antimicrobial activity,effectiveness in experimental infections, and pharmacologicalproperties, the tetracyclines as a class rapidly became widely used fortherapeutic purposes. However, this widespread use of tetracyclines forboth major and minor illnesses and diseases led directly to theemergence of resistance to these antibiotics even among highlysusceptible bacterial species both commensal and pathogenic (e.g.,pneumococci and Salmonella). The rise of tetracycline-resistantorganisms has resulted in a general decline in use of tetracyclines andtetracycline analogue compositions as antibiotics of choice.

SUMMARY OF THE INVENTION

[0005] The invention pertains, at least in part, to minocyclinecompounds of formula I:

[0006] wherein:

[0007] X is CHC(R¹³Y′Y), CR^(6′)R⁶, S, NR⁶, or O;

[0008] R², R^(4′), R^(4″), R^(7′) and R^(7″) are each hydrogen, alkyl,alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrugmoiety;

[0009] R⁴ is NR^(4′)R^(4″), alkyl, alkenyl, alkynyl, aryl, hydroxyl,halogen, or hydrogen;

[0010] R^(2′), R³, R¹⁰, R¹¹ and R¹² are each hydrogen or a pro-drugmoiety;

[0011] R⁵ is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl,heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy,or aryl carbonyloxy;

[0012] R⁶ and R^(6′) are independently hydrogen, methylene, absent,hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;

[0013] R⁹ is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl,arylalkynyl, thionitroso, or —(CH₂)₀₋₃NR^(9c)C(═Z′)ZR^(9a);

[0014] Z is CR^(9d)R^(9e), S, NR^(9b) or O;

[0015] Z′ is NR^(9f), O or S;

[0016] R^(9a), R^(9b),R^(9c), R^(9d), R^(9e) and R^(9f) are eachindependently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,heterocyclic, heteroaromatic or a prodrug moiety;

[0017] R⁸ is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl,alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,alkylamino, or an arylalkyl;

[0018] R¹³ is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;

[0019] Y′ and Y are each independently hydrogen, halogen, hydroxyl,cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, andpharmaceutically acceptable salts, esters and prodrugs thereof.

[0020] The invention also pertains, at least in part, to 9-substitutedminocycline compounds of the formula (II):

[0021] wherein:

[0022] R^(4′), R^(4″), R^(7′) and R^(7″) are each alkyl; and

[0023] R⁹ is a pyridylethynyl group; an alkenylcarbamate group; a halogroup; an alkylacrylate group; a naphthyl group; a haloacetyl group; analkyl carbamate group; a cyclopentyl or cyclopentenyl group; abenzofuranyl group; a phenylpropiononeamino group; a tosylamino group; amethoxypyridyl group; an alkeneamino group; an N-t-butyl group; at-butylamide group; a hydroxybutylamino group; a hydroxypropylaminogroup; a phenyl group; a nitrophenyl group; a nitrophenyl alkynyl group;an aminophenyl group; an alkoxyphenyl group; a halophenyl urea group; acyanophenyl group; a carboxyphenyl group; an acylphenyl group; analkylphenyl group; a halophenyl group; an alkoxyphenyl group; acarboxyalkylphenyl group; a phenylalkynyl group; an alkynyl group; analkylglycineethylester group; a styrene group; a thiophene group; and analkylaminophospho group; and pharmaceutically acceptable salts, estersand prodrugs thereof.

[0024] The invention also pertains to methods of using the minocyclinecompounds of the invention to treat subjects suffering from states whichcan treated using the minocycline compounds of the invention.

[0025] The invention also pertains to pharmaceutical compositionscomprising the minocycline compounds of the invention and apharmaceutically acceptable carrier. The invention also pertains to theuse of a minocycline compound of the invention for the manufacture of amedicament, e.g., a medicament for the treatment of a tetracyclineresponsive state.

DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention pertains, at least in part, to novel 9-substituted minocycline compounds. These minocycline compounds can beused to treat numerous tetracycline compound-responsive states, such asbacterial infections and neoplasms, as well as other known applicationsfor minocycline and tetracycline compounds in general, such as blockingtetracycline efflux and modulation of gene expression.

[0027] The invention pertains, at least in part, to minocyclinecompounds of Formula I:

[0028] wherein:

[0029] X is CHC(R¹³Y′Y), CR^(6′)R⁶, S, NR⁶, or O;

[0030] R², R^(4′), R^(4″), R^(7′) and R^(7″) are each hydrogen, alkyl,alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrugmoiety;

[0031] R⁴ is NR^(4′)R^(4″), alkyl, alkenyl, alkynyl, aryl, hydroxyl,halogen, or hydrogen;

[0032] R^(2′), R³, R¹⁰, R¹¹ and R¹² are each hydrogen or a pro-drugmoiety;

[0033] R⁵ is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl,heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy,or aryl carbonyloxy;

[0034] R⁶ and R^(6′) are independently hydrogen, methylene, absent,hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;

[0035] R⁹ is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl,arylalkynyl, thionitroso, or —(CH₂)₀₋₃NR^(9c)C(═Z′)ZR^(9a);

[0036] Z is CR^(9d)R^(9e), S, NR^(9b) or O;

[0037] Z′is NR^(9f), O or S;

[0038] R^(9a), R^(9b), R^(9c), R^(9d), R^(9e) and R^(9f) are eachindependently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,heterocyclic, heteroaromatic or a prodrug moiety;

[0039] R⁸ is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl,alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,alkylamino, or an arylalkyl;

[0040] R¹³ is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;

[0041] Y′ and Y are each independently hydrogen, halogen, hydroxyl,cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, andpharmaceutically acceptable salts, esters and prodrugs thereof.

[0042] The term minocycline compounds refers to compounds of formula (I)above. In an embodiment, the term minocycline compounds includecompounds wherein X is CR⁶R^(6′); R², R^(2′), R⁵, R⁶, R^(6′), R⁸,R⁹,R¹⁰, and R¹² are each hydrogen; R⁴ is NR^(4′)R^(4″); and R^(4′), R^(4″),R^(7′), and R^(7″) are each lower alkyl, e.g., methyl.

[0043] Examples of R⁹ include substituted and unsubstituted aryl groups.The aryl groups include substituted and unsubstituted heteroaryls (e.g.,furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl,isoquinolinyl, benzodioxazolyl, benzoxazolyl, benzothiazolyl,benzoimidazolyl, methylenedioxyphenyl, indolyl, thienyl, pyrimidyl,pyrazinyl, purinyl, pyrazolyl, oxazolyl, isooxazolyl, naphthridinyl,thiazolyl, isothiazolyl, or deazapurinyl), substituted or unsubstitutedphenyl, and groups with more than one aromatic ring, such as naphthyl.

[0044] Examples of substituents of R⁹ include, but are not limited to,alkyl, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy,alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl,arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl,arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl,aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato,phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl,alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato,sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl, alkylaryl,aryl and heteroaryl.

[0045] In a further embodiment, the aryl R⁹ group is substituted withone or more substituents such as, for example, carboxylate, alkyl,alkenyl, alkynyl, aryl, heterocyclic, cyano, amino, halogen, alkoxy,alkoxycarbonyl, amido, alkylcarbonyl, or nitro.

[0046] In another embodiment, R⁹ is substituted or unsubstitutedalkynyl. The alkynyl R⁹ group may be substituted with a substituted orunsubstituted aryl group, such as, for example, phenyl. The possiblesubstituents for the substituted phenyl group include, for example,those listed supra, for the aryl R⁹ group. Furthermore, the substitutedalkynyl R⁹ group may be substituted with a heteroaryl (e.g., pyridinyl),alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, etc.), alkenyl (e.g., ethenyl,propenyl, butenyl, pentenyl, hexenyl, etc.), carboxylate, silyl (e.g.,trialkylsilyl, e.g., trimethylsilyl), aralkyl, or a alkyloxycarbonylgroup.

[0047] Each of these groups may also be further substituted, with suchsubstituents as alkyl, alkenyl, halogen, hydroxyl, alkoxy,alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl,arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl,arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate,aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido,imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano, azido,heterocyclyl, alkylaryl, aryl and heteroaryl.

[0048] In a further embodiment, the alkynyl R⁹ group is substituted withan aminoalkyl group. The aminoalkyl group may then also be substitutedwith, for example, an alkyl, alkenyl, alkynyl, acyl, carbonyl, oralkylsulfone group.

[0049] In another further embodiment, the alkynyl R⁹ group issubstituted with a cycloalkenyl group, such as, for example,cyclopentene.

[0050] In another embodiment, R⁹ is alkyl. The alkyl group may besubstituted or unsubstituted. Examples of alkyl groups include, forexample, both straight chain, branched and cyclic alkyl groups. Forexample, alkyl groups include methyl, ethyl, i-propyl, n-propyl,i-butyl, n-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,etc. Cyclic alkyl groups include groups with one or more rings, such as,for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, etc. In an embodiment, the alkyl R⁹ group is2-cyclopentylethyl.

[0051] Examples of substituents of alkyl groups include, for example,halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl,alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy,perfluoromethoxy, perchloromethoxy, etc.), alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl,alkenylaminocarbonyl, carboxy, alkylcarbonyl, arylcarbonyl,arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfate, alkylsulfinyl, alkenyl, sulfonato, sulfamoyl,sulfonamido, nitro, alkenyl, cyano, azido, heterocyclyl, alkylaryl, aryland heteroaryl.

[0052] In another embodiment, the minocycline compound of the inventionis a compound wherein R⁹ is —NR^(9c)C(═Z′)ZR^(9a),—(CH₂)₂NR^(9c)C(═Z′)ZR^(9a), or —(CH₂)₂NR^(9c)C(═Z′)ZR^(9a). In certainembodiments, R⁹ is —NR^(9c)C(═Z′)ZR^(9a) or —CH₂NR^(9c)C(═Z′)ZR^(9a).Examples of R^(9c) include hydrogen. Z′ may be, for example, S, NH, orO. Examples of Z include NR^(9b) (e.g., when R^(9b) is hydrogen, alkyl,etc.), O or S.

[0053] Examples of R^(9a) groups include aryl groups such as substitutedand unsubstituted phenyl. Examples of possible substituents of arylR^(9a) groups include, but are not limited to, alkyl (e.g., methyl,ethyl, propyl, butyl, pentyl, hexyl, perfluornethyl, perchloroethyl,etc.), alkenyl, halogen (e.g., fluorine, chlorine, bromine, iodine,etc.), hydroxyl, alkoxy (e.g., methoxy, ethoxy, propoxy,perfluoromethoxy, perchloromethoxy, etc.), alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl,alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl,alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl,alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino,acylamino, amido, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, acetyl, alkyl, cyano, azido, heterocyclyl,alkylaryl, aryl and heteroaryl groups.

[0054] In certain embodiments, at least one of the substituents of thesubstituted phenyl is nitro, alkoxy (e.g., methoxy, methylenedioxy,perfluoromethoxy) alkyl (e.g., methyl, ethyl, propyl, butyl, or pentyl),acetyl, halogen (e.g., fluorine, chlorine, bromine, or iodine), or amino(e.g, dialkylamino). In certain embodiments, the alkoxy group isperhalogenated, e.g., perfluoromethoxy.

[0055] Examples of aryl R^(9a) groups include, but are not limited to,unsubstituted phenyl, para-nitrophenyl, para-methoxy phenyl,para-perfluoromethoxy phenyl, para-acetyl phenyl, 3,5-methylenedioxyphenyl, 3,5-diperfluoromethyl phenyl, para-bromo phenyl,para-chloro phenyl, and para-fluoro phenyl.

[0056] Other examples of aryl R^(9a) groups include substituted andunsubstituted heterocycles (e.g., furanyl, imidazolyl, benzothiophenyl,benzofuranyl, quinolinyl, isoquinolinyl, benzodioxazolyl, benzoxazolyl,benzothiazolyl, benzoimidazolyl, methylenedioxyphenyl, indolyl, thienyl,pyrimidyl, pyrazinyl, purinyl, pyrazolyl, pyrolidinyl, oxazolyl,isooxazolyl, naphthridinyl, thiazolyl, isothiazolyl, or deazapurinyl)and substituted and unsubstituted biaryl groups, such as naphthyl andfluorene.

[0057] R^(9a) also may be substituted or unsubstituted alkyl, e.g,methyl, ethyl, propyl, butyl, pentyl, etc. Examples of substituentsinclude but are not limited to halogens (e.g, fluorine, bromine,chlorine, iodine, etc.), hydroxyl, alkoxy (e.g., methoxy, ethoxy,propoxy, butoxy, etc.), alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate,phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino,sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, alkenyl, heterocyclyl, alkylaryl, aryland heteroaryl.

[0058] R^(9a) also can be substituted or unsubstituted alkenyl. Examplesof substituents for alkenyl R^(9a) groups include those listed above foralkyl R^(9a) groups. Examples of alkenyl R^(9a) groups includepent-1-enyl.

[0059] In an embodiment, Z′ is NH, Z is NH, and R^(9a) is alkyl.

[0060] The invention also pertains to compounds wherein R⁹ is aminoalkyl(e.g, aminomethyl). Aminoalkyl R⁹ groups may be further substituted.Examples of substituents include aryl groups, such as, for examplesubstituted or unsubstituted phenyl (e.g., methylenedioxyphenyl orpara-perfluoromethoxyphenyl), or heteroaromatic groups which allows thecompound of the invention to perform its intended function.

[0061] Examples of minocycline compounds of the invention include thoselisted in Table 1, as well as the ones listed below:

[0062] Pharmaceutically acceptable salts of these compounds are alsoincluded. Other compound of the invention are listed in Table 1.

[0063] The invention also relates, at least in part, to 9-substitutedminocycline compounds of the formula:

[0064] wherein:

[0065] R^(4′), R^(4″), R^(7′), and R^(7″)are each alkyl; and

[0066] R⁹ is a pyridylethynyl group; an alkenylcarbamate group; a halogroup; an alkylacrylate group; a naphthyl urea group; a haloacetylgroup; an alkyl carbamate group; a cyclopentyl or cyclopentenyl group; abenzofuranyl group; a phenylpropiononeamino group; a tosylamino group; amethoxypyridyl group; an alkeneamino group; an N-t-butyl group; at-butylamide group; a hydroxybutylamino group; a hydroxypropylaminogroup; a phenyl group; a nitrophenyl group; a nitrophenyl alkynyl group;an aminophenyl group; a halophenyl urea group; an alkoxyphenyl group; acyanophenyl group; a carboxyphenyl group; an acylphenyl group; analkylphenyl group; a halophenyl group; an alkoxyphenyl group; acarboxyalkylphenyl group; a phenylalkynyl group; an alkynyl group; analkylglycineethylester group; a styrene group; a thiophene group; analkylaminophospho group; and pharmaceutically acceptable salts thereof.

[0067] The term “9-substituted minocycline compound” includesminocycline compounds with a substituent at the 9 position. In anotherembodiment, the compound is a derivative of minocycline.

[0068] In an embodiment, R⁹ is an alkenylcarbamate group. Examples oftetracycline compounds with this R⁹ substituent include 9-isopropenylcarbamate minocycline.

[0069] In an embodiment, R⁹ is a pyridylethynyl group. Examples oftetracycline compounds with this R⁹ substituent include9-(2-pyridylethynyl)minocycline.

[0070] In an embodiment, R⁹ is a halo group. Examples of tetracyclinecompounds with this R⁹ substituent include 9-iodo minocycline.

[0071] In an embodiment, R⁹ is an alkylacrylate group. Examples oftetracycline compounds with this R⁹ substituent include 9-butylacrylateminocycline.

[0072] In an embodiment, R⁹ is a naphthyl urea group. Examples oftetracycline compounds with this R⁹substituent include 9-naphthylminocycline urea.

[0073] In an embodiment, R⁹ is a haloacetyl group. Examples oftetracycline compounds with this R⁹ substituent include 9-chloroacetylminocycline urea.

[0074] In an embodiment, R⁹ is an alkyl carbamate group. Examples oftetracycline compounds with this R⁹ substituent include 9-neopentylminocycline carbamate.

[0075] In an embodiment, R⁹ is a cyclopentyl or cyclopentenyl group.Examples of tetracycline compounds with this R⁹ substituent include9-cyclopentene minocycline.

[0076] In an embodiment, R⁹ is a benzofuranyl group. Examples oftetracycline compounds with this R⁵ substituent include 9-benzofuranylminocycline.

[0077] In an embodiment, R⁹ is a phenylpropiononeamino group. Examplesof tetracycline compounds with this R⁹ substituent include9-(phenylpropiononeamino)minocycline.

[0078] In an embodiment, R⁹ is a tosylamino group. Examples oftetracycline compounds with this R⁹ substituent include 9-tosylaminominocycline.

[0079] In an embodiment, R⁹ is a methoxypyridyl group. Examples oftetracycline compounds with this R⁵ substituent include9-(2-methoxy-3-pyridyl)minocycline.

[0080] In an embodiment, R⁵ is an alkeneamino group. Examples oftetracycline compounds with this R⁹ substituent include9-(N-2′-hydroxydecyl-9′-ene-amino)minocycline.

[0081] In an embodiment, R⁹ is an N-t-butyl group. Examples oftetracycline compounds with this R⁹ substituent includeN-t-butyl-minocycline HCl.

[0082] In an embodiment, R⁹ is a t-butylamide group. Examples oftetracycline compounds with this R⁹ substituent include 9-BOC-NHminocycline.

[0083] In an embodiment, R⁹ is a hydroxybutylamino group. Examples oftetracycline compounds with this R⁹ substituent include9-(N-2′-hydroxybutylamino)minocycline.

[0084] In an embodiment, R⁹ is a hydroxypropylamino group. Examples oftetracycline compounds with this R⁹ substituent include 9-(N-3-chloro,2-hydroxylpropylamino) minocycline.

[0085] In an embodiment, R⁹ is a phenyl group. Examples of tetracyclinecompounds with this R⁹ substituent include 9-phenyl minocycline HCl and9-p-tolyl minocycline.

[0086] In an embodiment, R⁹ is a nitrophenyl group. Examples oftetracycline compounds with this R⁹ substituent include9-(3′-nitrophenyl)minocycline.

[0087] In an embodiment, R⁹ is a nitrophenyl alkynyl group. Examples oftetracycline compounds with this R⁹ substituent include9-(4′-nitrophenylethynyl)minocycline.

[0088] In an embodiment, R⁹ is an aminophenyl group. Examples oftetracycline compounds with this R⁹ substituent include9-(3-aminophenyl)minocycline.

[0089] In an embodiment, R⁹ is a halophenyl urea group;. Examples oftetracycline compounds with this R⁹ substituent include9-(4-chloro,2-trifluoromethylphenyl)minocycline urea.

[0090] In an embodiment, R⁹ is an alkoxyphenyl group. Examples oftetracycline compounds with this R⁹ substituent include9-(p-methoxyphenyl)minocycline, 9-(4′-methoxyphenyl) minocycline, and9-(3,4-methylenedioxyphenyl)minocycline.

[0091] In an embodiment, R⁹ is a cyanophenyl group. Examples oftetracycline compounds with this R⁹ substituent include9-(4′-cyanophenyl)minocycline.

[0092] In an embodiment, R⁹ is a carboxyalkylphenyl group. Examples oftetracycline compounds with this R⁹ substituent include9-(4′-carboxyphenyl)minocycline.

[0093] In an embodiment, R⁹ is an acylphenyl group. Examples oftetracycline compounds with this R⁹ substituent include9-(3-formylphenyl)minocycline.

[0094] In an embodiment, R⁹ is an alkylphenyl group. Examples oftetracycline compounds with this R⁹ substituent include9-(4′-t-butylphenyl)minocycline.

[0095] In an embodiment, R⁹ is a halophenyl group. Examples oftetracycline compounds with this R⁹ substituent include9-(3-chlorophenyl)minocycline, 9-(2′,4′-difluorophenyl) minocycline,9-(3,4-difluorophenyl)minocycline, 9-(4′-chlorophenyl)minocycline,9-(3,4-dichlorophenyl) minocycline, and9-(4′-trifluoromethylphenyl)minocycline.

[0096] In an embodiment, R⁹ is an alkoxyphenyl group. Examples oftetracycline compounds with this R⁹ substituent include9-(3-ethoxyphenyl)minocycline.

[0097] In an embodiment, R⁹ is a carboxyalkylphenyl group. Examples oftetracycline compounds with this R⁹ substituent include9-(4-carboxymethylphenyl)minocycline.

[0098] In an embodiment, R⁹ is a phenylalkynyl group. Examples oftetracycline compounds with this R⁹ substituent include9-(phenylethynyl)minocycline, 9-(3-hydroxyphenylethynyl) minocycline,9-(p-tolylethynyl)minocycline, and9-(p-methoxyphenylethynyl)minocycline.

[0099] In an embodiment, R⁹ is an alkynyl group. Examples oftetracycline compounds with this R⁹ substituent include 9-ethynylminocycline, 9-(p-fluoroethynyl)minocycline, 9-(trimethylsilylethynyl)minocycline, 9-(propionyl)minocycline, 9-(cyclohexenylethynyl)minocycline, and 9-(11-cyclohexyl- 1-hydroxyethynyl)minocycline.

[0100] In an embodiment, R⁹ is an alkylglycineethylester group. Examplesof tetracycline compounds with this R⁹ substituent include9-propylglycineethylester minocycline HCl, and 9-methylglycineethylesterminocycline.

[0101] In an embodiment, R⁹ is a styrene group. Examples of tetracyclinecompounds with this R⁹ substituent include 9-(styrene)minocycline,9-(4′-fluorostyrene)minocycline.

[0102] In an embodiment, R⁹ is a thiophene group. Examples oftetracycline compounds with this R⁹ substituent include9-(2thiophene)minocycline, and 9-(5′-chloro-2′-thiophene) minocycline.

[0103] In an embodiment, R⁹ is an alkylaminophospho group. Examples oftetracycline compounds with this R⁹ substituent include9-(p-methoxyphenylaminophospho)minocycline, and9-(phenylaminophospho)minocycline.

[0104] The minocycline compounds of this invention can be synthesizedusing the methods described in Schemes 1-6.

[0105] 9-substituted minocyclines can be synthesized by the followinggeneral method, shown in Scheme 1.

[0106] Generally, 9-substituted minocycline compounds can be synthesizedas shown in Scheme 2 by treating minocycline (1A), with sulfuric acidand sodium nitrate. The resulting product is 9-nitro (1B)minocycline.The nitro minocycline compound is then treated with hydrogen gas and aplatinum catalyst to yield the 9-amino minocycline compound, 1C. Tosynthesize 9 derivatives, the 9-amino minocycline compound is treatedwith HONO, to yield the diazonium salt (ID). The salt can subsequentlybe treated with numerous compounds possessing an alkene or H bondfunctional group such as alkenes, aryls, and alkynyls (e.g., R⁹Br)yielding the 9-substituted minocycline compound (1E).

[0107] As shown in Scheme 3, minocycline compounds of the inventionwherein R⁹ is a carbamate or a urea derivative can be synthesized usingthe following protocol. Minocycline (2A) is treated with NaNO₂ underacidic conditions forming 9-nitro minocycline (2B). 9-nitrominocycline(2B) is then treated with H₂ gas and a platinum catalyst to form the9-amino minocycline derivative (2 C). To form the urea derivative (2E),isocyanate (2D) is reacted with the 9-amino minocycline derivative (2C).To form the carbamate (2G), the appropriate acid chloride ester (2F) isreacted with 2C.

[0108] As shown in Scheme 3, minocycline compounds of the invention,wherein R⁹ is a heterocyclic (i.e. thiazole) substituted amino group canbe synthesized using the above protocol. 9-amino minocycline (3A) isreacted with Fmoc-isothiocyanate (3B) to produce the protected thiourea(3C). The protected thiourea (3C) is then deprotected yielding theactive tetracycline urea or tetracycline thiourea (3D) compound. Thetetracycline thiourea (3D) is reacted with an α-haloketone (3E) toproduce a thiazole substituted 9-amino minocycline (3F).

[0109] As shown in Scheme 4, 9-alkenyl minocycline compounds (4A) can behydrogenated to form alkyl 9-substituted minocycline compounds (4B).Scheme 4 depicts the selective hydrogenation of the 9-position doublebond, with hydrogen gas and a palladium/carbon catalyst. Similarly,9-alkynyl minocyclines also can be hydrogenated to form 9-alkylminocycline compounds.

[0110] In Scheme 5, a general synthetic scheme for synthesizing9-position aryl derivatives of a minocycline compound is shown. InScheme 5, a Suzuki coupling of an aryl boronic acid with aniodominocycline compound is shown. An iodo minocycline compound (5B) canbe synthesized from sancycline by treating minocycline (5A) with atleast one equivalent N-iodosuccinimide (NIS) under acidic conditions.The reaction is quenched, and the resulting 9-iodo minocycline (5B) canthen be purified using standard techniques known in the art. To form thearyl derivative, 9-iodo minocycline (5B) is treated with boronic acid(5C) plus aqueous sodium carbonate, and is catalyzed with palladium. Theproduct (5D) can be purified by methods known in the art (such as HPLC).Other 9-aryl minocycline compounds can be synthesized using similarprotocols.

[0111] The 9-substituted minocycline compounds of the invention can alsobe synthesized using Stille cross couplings. Stille cross couplings canbe performed using an appropriate tin reagent (e.g., R-SnBu₃) and ahalogenated tetracycline compound, (e.g., 9-iodominocycline). The tinreagent and the iodominocycline compound can be treated with a palladiumcatalyst (e.g., Pd(PPh₃)₂Cl₂ or Pd(AsPh₃)₂Cl₂) and, optionally, with anadditional copper salt, e.g CuI.

[0112] The resulting compound can then be purified using techniquesknown in the art.

[0113] The compounds of the invention can also be synthesized usingHeck-type cross coupling reactions. As shown in Scheme 6, Heck-typecross-couplings can be performed using a halogenated tetracyclinecompound (e.g., 9-iodominocycline, 6A), a reactive alkene (6B) or alkyne(6D), and an appropriate palladium or other transition metal catalyst.The resulting 9-substituted alkenyl (6C) or 9-substituted alkynyl(6E)minocycline compound can then be purified using techniques known inthe art.

[0114] The term “alkyl” includes saturated aliphatic groups, includingstraight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups(isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups(cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkylsubstituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.The term alkyl further includes alkyl groups, which can further includeoxygen, nitrogen, sulfur or phosphorous atoms replacing one or morecarbons of the hydrocarbon backbone. In certain embodiments, a straightchain or branched chain alkyl has 6 or fewer carbon atoms in itsbackbone (e.g., C₁-C₆ for straight chain, C₃-C₆ for branched chain), andmore preferably 4 or fewer. Likewise, preferred cycloalkyls have from3-8 carbon atoms in their ring structure, and more preferably have 5 or6 carbons in the ring structure. The term C₁-C₆ includes alkyl groupscontaining 1 to 6 carbon atoms.

[0115] Moreover, the term alkyl includes both “unsubstituted alkyls” and“substituted alkyls”, the latter of which refers to alkyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example,alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Cycloalkyls can be further substituted, e.g.,with the substituents described above. An “alkylaryl” or an “arylalkyl”moiety is an alkyl substituted with an aryl (e.g., phenylmethyl(benzyl)). The term “alkyl” also includes the side chains of natural andunnatural amino acids.

[0116] The term “aryl” includes groups, including 5- and 6-memberedsingle-ring aromatic groups that may include from zero to fourheteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene,thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole,oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, andthe like. Furthermore, the term “aryl” includes multicyclic aryl groups,e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole,benzodioxazole, benzothiazole, benzoimidazole, benzothiophene,methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole,benzofuran, purine, benzofuran, deazapurine, or indolizine. Those arylgroups having heteroatoms in the ring structure may also be referred toas “aryl heterocycles”, “heterocycles,” “heteroaryls” or“heteroaromatics”. The aromatic ring can be substituted at one or morering positions with such substituents as described above, as forexample, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Aryl groups can also be fused or bridged withalicyclic or heterocyclic rings which are not aromatic so as to form apolycycle (e.g., tetralin).

[0117] The term “alkenyl” includes unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one double bond.

[0118] For example, the term “alkenyl” includes straight-chain alkenylgroups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl,octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups,cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substitutedcycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenylgroups. The term alkenyl further includes alkenyl groups which includeoxygen, nitrogen, sulfur or phosphorous atoms replacing one or morecarbons of the hydrocarbon backbone. In certain embodiments, a straightchain or branched chain alkenyl group has 6 or fewer carbon atoms in itsbackbone (e.g., C₂-C₆ for straight chain, C₃-C₆ for branched chain).Likewise, cycloalkenyl groups may have from 3-8 carbon atoms in theirring structure, and more preferably have 5 or 6 carbons in the ringstructure. The term C₂-C₆ includes alkenyl groups containing 2 to 6carbon atoms.

[0119] Moreover, the term alkenyl includes both “unsubstituted alkenyls”and “substituted alkenyls”, the latter of which refers to alkenylmoieties having substituents replacing a hydrogen on one or more carbonsof the hydrocarbon backbone. Such substituents can include, for example,alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

[0120] The term “alkynyl” includes unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but which contain at least one triple bond.

[0121] For example, the term “alkynyl” includes straight-chain alkynylgroups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl,octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, andcycloalkyl or cycloalkenyl substituted alkynyl groups. The term alkynylfurther includes alkynyl groups which include oxygen, nitrogen, sulfuror phosphorous atoms replacing one or more carbons of the hydrocarbonbackbone. In certain embodiments, a straight chain or branched chainalkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C₂-C₆for straight chain, C₃-C₆ for branched chain). The term C₂-C₆ includesalkynyl groups containing 2 to 6 carbon atoms.

[0122] Moreover, the term alkynyl includes both “unsubstituted alkynyls”and “substituted alkynyls”, the latter of which refers to alkynylmoieties having substituents replacing a hydrogen on one or more carbonsof the hydrocarbon backbone. Such substituents can include, for example,alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

[0123] Unless the number of carbons is otherwise specified, “loweralkyl” as used herein means an alkyl group, as defined above, but havingfrom one to five carbon atoms in its backbone structure. “Lower alkenyl”and “lower alkynyl” have chain lengths of, for example, 2-5 carbonatoms.

[0124] The term “acyl” includes compounds and moieties which contain theacyl radical (CH₃CO— ) or a carbonyl group. The term “substituted acyl”includes acyl groups where one or more of the hydrogen atoms arereplaced by for example, alkyl groups, alkynyl groups, halogens,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano,amino (including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0125] The term “acylamino” includes moieties wherein an acyl moiety isbonded to an amino group. For example, the term includesalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

[0126] The term “aroyl” includes compounds and moieties with an aryl orheteroaromatic moiety bound to a carbonyl group. Examples of aroylgroups include phenylcarboxy, naphthyl carboxy, etc.

[0127] The terms “alkoxyalkyl”, “alkylaminoalkyl” and “thioalkoxyalkyl”include alkyl groups, as described above, which further include oxygen,nitrogen or sulfur atoms replacing one or more carbons of thehydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.

[0128] The term “alkoxy” includes substituted and unsubstituted alkyl,alkenyl, and alkynyl groups covalently linked to an oxygen atom.Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy,propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxygroups include halogenated alkoxy groups. The alkoxy groups can besubstituted with groups such as alkenyl, alkynyl, halogen, hydroxyl,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano,amino (including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.Examples of halogen substituted alkoxy groups include, but are notlimited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy,chloromethoxy, dichloromethoxy, trichloromethoxy, etc.

[0129] The term “amine” or “amino” includes compounds where a nitrogenatom is covalently bonded to at least one carbon or heteroatom. The term“alkyl amino” includes groups and compounds wherein the nitrogen isbound to at least one additional alkyl group. The term “dialkyl amino”includes groups wherein the nitrogen atom is bound to at least twoadditional alkyl groups. The term “arylamino” and “diarylamino” includegroups wherein the nitrogen is bound to at least one or two aryl groups,respectively. The term “alkylarylamino,” “alkylaminoaryl” or“arylaminoalkyl” refers to an amino group which is bound to at least onealkyl group and at least one aryl group. The term “alkaminoalkyl” refersto an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which isalso bound to an alkyl group.

[0130] The term “amide” or “aminocarbonyl” includes compounds ormoieties which contain a nitrogen atom which is bound to the carbon of acarbonyl or a thiocarbonyl group. The term includes “alkaminocarbonyl”or “alkylaminocarbonyl” groups which include alkyl, alkenyl, aryl oralkynyl groups bound to an amino group bound to a carbonyl group. Itincludes arylaminocarbonyl groups which include aryl or heteroarylmoieties bound to an amino group which is bound to the carbon of acarbonyl or thiocarbonyl group. The terms “alkylaminocarbonyl,”“alkenylaminocarbonyl,” “alkynylaminocarbonyl,” “arylaminocarbonyl,”“alkylcarbonylamino,” “alkenylcarbonylamino,” “alkynylcarbonylamino,”and “arylcarbonylamino” are included in term “amide.” Amides alsoinclude urea groups (aminocarbonylamino) and carbamates(oxycarbonylamino).

[0131] The term “carbonyl” or “carboxy” includes compounds and moietieswhich contain a carbon connected with a double bond to an oxygen atom.Examples of moieties which contain a carbonyl include aldehydes,ketones, carboxylic acids, amides, esters, anhydrides, etc.

[0132] The term “thiocarbonyl” or “thiocarboxy” includes compounds andmoieties which contain a carbon connected with a double bond to a sulfuratom.

[0133] The term “ether” includes compounds or moieties which contain anoxygen bonded to two different carbon atoms or heteroatoms. For example,the term includes “alkoxyalkyl” which refers to an alkyl, alkenyl, oralkynyl group covalently bonded to an oxygen atom which is covalentlybonded to another alkyl group.

[0134] The term “ester” includes compounds and moieties which contain acarbon or a heteroatom bound to an oxygen atom which is bonded to thecarbon of a carbonyl group. The term “ester” includes alkoxycarboxygroups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynylgroups are as defined above.

[0135] The term “thioether” includes compounds and moieties whichcontain a sulfur atom bonded to two different carbon or hetero atoms.Examples of thioethers include, but are not limited to alkthioalkyls,alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” includecompounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfuratom which is bonded to an alkyl group. Similarly, the term“alkthioalkenyls” and “alkthioalkynyls” refer to compounds or moietieswherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atomwhich is covalently bonded to an alkynyl group.

[0136] The term “hydroxy” or “hydroxyl” includes groups with an —OH or—O⁻.

[0137] The term “halogen” includes fluorine, bromine, chlorine, iodine,etc. The term “perhalogenated” generally refers to a moiety wherein allhydrogens are replaced by halogen atoms.

[0138] The terms “polycyclyl” or “polycyclic radical” refer to two ormore cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls,aryls and/or heterocyclyls) in which two or more carbons are common totwo adjoining rings, e.g., the rings are “fused rings”. Rings that arejoined through non-adjacent atoms are termed “bridged” rings. Each ofthe rings of the polycycle can be substituted with such substituents asdescribed above, as for example, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl,arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl,arylcarbonyl, arylalkyl carbonyl, alkenylcarbonyl, aminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano,amino (including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0139] The term “heteroatom” includes atoms of any element other thancarbon or hydrogen.

[0140] Preferred heteroatoms are nitrogen, oxygen, sulfur andphosphorus.

[0141] The term “prodrug moiety” includes moieties which can bemetabolized in vivo to a hydroxyl group and moieties which mayadvantageously remain esterified in vivo. Preferably, the prodrugsmoieties are metabolized in vivo by esterases or by other mechanisms tohydroxyl groups or other advantageous groups. Examples of prodrugs andtheir uses are well known in the art (See, e.g., Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19). The prodrugs can beprepared in situ during the final isolation and purification of thecompounds, or by separately reacting the purified compound in its freeacid form or hydroxyl with a suitable esterifying agent. Hydroxyl groupscan be converted into esters via treatment with a carboxylic acid.Examples of prodrug moieties include substituted and unsubstituted,branch or unbranched lower alkyl ester moieties, (e.g., propionoic acidesters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters(e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g.,acetyloxymethyl ester), acyloxy lower alkyl esters (e.g.,pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkylesters (e.g., benzyl ester), substituted (e.g., with methyl, halo, ormethoxy substituents) aryl and aryl-lower alkyl esters, amides,lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Preferredprodrug moieties are propionoic acid esters and acyl esters.

[0142] It will be noted that the structure of some of the minocyclinecompounds of this invention includes asymmetric carbon atoms. It is tobe understood accordingly that the isomers arising from such asymmetry(e.g., all enantiomers and diastereomers) are included within the scopeof this invention, unless indicated otherwise. Such isomers can beobtained in substantially pure form by classical separation techniquesand by stereochemically controlled synthesis. Furthermore, thestructures and other compounds and moieties discussed in thisapplication also include all tautomers thereof.

[0143] The invention also pertains to methods for treating atetracycline responsive states in subjects, by administering to asubject an effective amount of a minocycline compound of the invention(e.g., a compound of Formula (I), (II) or shown in Table 1), such thatthe tetracycline responsive state is treated.

[0144] The language “tetracycline compound responsive state” includesstates which can be treated, prevented, or otherwise ameliorated by theadministration of a minocycline compound of the invention. Tetracyclinecompound responsive states include bacterial infections (including thosewhich are resistant to other tetracycline compounds), cancer, diabetes,and other states for which tetracycline compounds have been found to beactive (see, for example, U.S. Pat. Nos. 5,789,395; 5,834,450; and5,532,227). Compounds of the invention can be used to prevent or controlimportant mammalian and veterinary diseases such as diarrhea, urinarytract infections, infections of skin and skin structure, ear, nose andthroat infections, wound infection, mastitis and the like. In addition,methods for treating neoplasms using tetracycline compounds of theinvention are also included (van der Bozert et al., Cancer Res.,48:6686-6690 (1988)). For certain tetracycline responsive state, aminocycline compound of the invention with little or no antibacterialactivity may be desirable.

[0145] Bacterial infections may be caused by a wide variety of grampositive and gram negative bacteria. The compounds of the invention areuseful as antibiotics against organisms which are resistant to othertetracycline compounds. The antibiotic activity of the tetracyclinecompounds of the invention may be determined using the method discussedin Example 2, or by using the in vitro standard broth dilution methoddescribed in Waitz, J. A., National Commission for Clinical LaboratoryStandards, Document M7-A2, vol. 10, no. 8, pp. 13-20, 2^(nd) edition,Villanova, Pa. (1990).

[0146] The minocycline compounds may also be used to treat infectionstraditionally treated with tetracycline compounds such as, for example,rickettsiae; a number of gram-positive and gram-negative bacteria; andthe agents responsible for lymphogranuloma venereum, inclusionconjunctivitis, psittacosis. The tetracycline compounds may be used totreat infections of, e.g., K pneumoniae, Salmonella, E. hirae, A.baumanii, B. catarrhalis, H influenzae, P. aeruginosa, E. faecium, E.coli, S. aureus or E. faecalis. In one embodiment, the minocyclinecompound is used to treat a bacterial infection that is resistant toother tetracycline antibiotic compounds. The minocycline compound of theinvention may be administered with a pharmaceutically acceptablecarrier.

[0147] The language “effective amount” of the compound is that amountnecessary or sufficient to treat or prevent a tetracycline compoundresponsive state. The effective amount can vary depending on suchfactors as the size and weight of the subject, the type of illness, orthe particular minocycline compound. For example, the choice of theminocycline compound can affect what constitutes an “effective amount”.One of ordinary skill in the art would be able to study theaforementioned factors and make the determination regarding theeffective amount of the minocycline compound without undueexperimentation.

[0148] The invention also pertains to methods of treatment againstmicroorganism infections and associated diseases. The methods includeadministration of an effective amount of one or more minocyclinecompounds to a subject. The subject can be either a plant or,advantageously, an animal, e.g., a mammal, e.g., a human.

[0149] In the therapeutic methods of the invention, one or moreminocycline compounds of the invention may be administered alone to asubject, or more typically a compound of the invention will beadministered as part of a pharmaceutical composition in mixture withconventional excipient, i.e., pharmaceutically acceptable organic orinorganic carrier substances suitable for parenteral, oral or otherdesired administration and which do not deleteriously react with theactive compounds and are not deleterious to the recipient thereof.

[0150] The invention also pertains to pharmaceutical compositionscomprising a therapeutically effective amount of a minocycline compoundand, optionally, a pharmaceutically acceptable carrier.

[0151] The language “pharmaceutically acceptable carrier” includessubstances capable of being coadministered with the minocyclinecompound(s), and which allow both to perform their intended function,e.g., treat or prevent a tetracycline responsive state. Suitablepharmaceutically acceptable carriers include but are not limited towater, salt solutions, alcohol, vegetable oils, polyethylene glycols,gelatin, lactose, amylose, magnesium stearate, talc, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, etc. The pharmaceutical preparations can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, colorings, flavorings and/oraromatic substances and the like which do not deleteriously react withthe active compounds of the invention.

[0152] The minocycline compounds of the invention that are basic innature are capable of forming a wide variety of salts with variousinorganic and organic acids. The acids that may be used to preparepharmaceutically acceptable acid addition salts of the minocyclinecompounds of the invention that are basic in nature are those that formnon-toxic acid addition salts, i.e., salts containing pharmaceuticallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate,acetate, lactate, salicylate, citrate, acid citrate, tartrate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and palmoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts. Although such saltsmust be pharmaceutically acceptable for administration to a subject,e.g., a mammal, it is often desirable in practice to initially isolate aminocycline compound of the invention from the reaction mixture as apharmaceutically unacceptable salt and then simply convert the latterback to the free base compound by treatment with an alkaline reagent andsubsequently convert the latter free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent, such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is readily obtained. The preparation ofother minocycline compounds of the invention not specifically describedin the foregoing experimental section can be accomplished usingcombinations of the reactions described above that will be apparent tothose skilled in the art.

[0153] The preparation of other minocycline compounds of the inventionnot specifically described in the foregoing experimental section can beaccomplished using combinations of the reactions described above thatwill be apparent to those skilled in the art.

[0154] The minocycline compounds of the invention that are acidic innature are capable of forming a wide variety of base salts. The chemicalbases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those minocycline compounds of the inventionthat are acidic in nature are those that form non-toxic base salts withsuch compounds. Such non-toxic base salts include, but are not limitedto those derived from such pharmaceutically acceptable cations such asalkali metal cations (e.g., potassium and sodium) and alkaline earthmetal cations (e.g., calcium and magnesium), ammonium or water-solubleamine addition salts such as N-methylglucamine-(meglumine), and thelower alkanolammonium and other base salts of pharmaceuticallyacceptable organic amines. The pharmaceutically acceptable base additionsalts of minocycline compounds of the invention that are acidic innature may be formed with pharmaceutically acceptable cations byconventional methods. Thus, these salts may be readily prepared bytreating the minocycline compound of the invention with an aqueoussolution of the desired pharmaceutically acceptable cation andevaporating the resulting solution to dryness, preferably under reducedpressure. Alternatively, a lower alkyl alcohol solution of theminocycline compound of the invention may be mixed with an alkoxide ofthe desired metal and the solution subsequently evaporated to dryness.

[0155] The preparation of other minocycline compounds of the inventionnot specifically described in the foregoing experimental section can beaccomplished using combinations of the reactions described above thatwill be apparent to those skilled in the art.

[0156] The minocycline compounds of the invention and pharmaceuticallyacceptable salts thereof can be administered via either the oral,parenteral or topical routes. In general, these compounds are mostdesirably administered in effective dosages, depending upon the weightand condition of the subject being treated and the particular route ofadministration chosen. Variations may occur depending upon the speciesof the subject being treated and its individual response to saidmedicament, as well as on the type of pharmaceutical formulation chosenand the time period and interval at which such administration is carriedout.

[0157] The pharmaceutical compositions of the invention may beadministered alone or in combination with other known compositions fortreating tetracycline responsive states in a subject, e.g., a mammal.Preferred mammals include pets (e.g., cats, dogs, ferrets, etc.), farmanimals (cows, sheep, pigs, horses, goats, etc.), lab animals (rats,mice, monkeys, etc.), and primates (chimpanzees, humans, gorillas). Thelanguage “in combination with” a known composition is intended toinclude simultaneous administration of the composition of the inventionand the known composition, administration of the composition of theinvention first, followed by the known composition and administration ofthe known composition first, followed by the composition of theinvention. Any of the therapeutically composition known in the art fortreating tetracycline responsive states can be used in the methods ofthe invention.

[0158] The minocycline compounds of the invention may be administeredalone or in combination with pharmaceutically acceptable carriers ordiluents by any of the routes previously mentioned, and theadministration may be carried out in single or multiple doses. Forexample, the novel therapeutic agents of this invention can beadministered advantageously in a wide variety of different dosage forms,i.e., they may be combined with various pharmaceutically acceptableinert carriers in the form of tablets, capsules, lozenges, troches, hardcandies, powders, sprays, creams, salves, suppositories, jellies, gels,pastes, lotions, ointments, aqueous suspensions, injectable solutions,elixirs, syrups, and the like. Such carriers include solid diluents orfillers, sterile aqueous media and various non-toxic organic solvents,etc. Moreover, oral pharmaceutical compositions can be suitablysweetened and/or flavored. In general, the therapeutically-effectivecompounds of this invention are present in such dosage forms atconcentration levels ranging from about 5.0% to about 70% by weight.

[0159] For oral administration, tablets containing various excipientssuch as microcrystalline cellulose, sodium citrate, calcium carbonate,dicalcium phosphate and glycine may be employed along with variousdisintegrants such as starch (and preferably corn, potato or tapiocastarch), alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatin capsules; preferred materials in this connection alsoinclude lactose or milk sugar as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various like combinations thereof.

[0160] For parenteral administration (including intraperitoneal,subcutaneous, intravenous, intradermal or intramuscular injection),solutions of a therapeutic compound of the present invention in eithersesame or peanut oil or in aqueous propylene glycol may be employed. Theaqueous solutions should be suitably buffered (preferably pH greaterthan 8) if necessary and the liquid diluent first rendered isotonic.These aqueous solutions are suitable for intravenous injection purposes.The oily solutions are suitable for intraarticular, intramuscular andsubcutaneous injection purposes. The preparation of all these solutionsunder sterile conditions is readily accomplished by standardpharmaceutical techniques well known to those skilled in the art. Forparenteral application, examples of suitable preparations includesolutions, preferably oily or aqueous solutions as well as suspensions,emulsions, or implants, including suppositories. Therapeutic compoundsmay be formulated in sterile form in multiple or single dose formatssuch as being dispersed in a fluid carrier such as sterile physiologicalsaline or 5% saline dextrose solutions commonly used with injectables.

[0161] Additionally, it is also possible to administer the compounds ofthe present invention topically when treating inflammatory conditions ofthe skin. Examples of methods of topical administration includetransdermal, buccal or sublingual application. For topical applications,therapeutic compounds can be suitably admixed in a pharmacologicallyinert topical carrier such as a gel, an ointment, a lotion or a cream.Such topical carriers include water, glycerol, alcohol, propyleneglycol, fatty alcohols, triglycerides, fatty acid esters, or mineraloils. Other possible topical carriers are liquid petrolatum,isopropylpalmitate, polyethylene glycol, ethanol 95%, polyoxyethylenemonolauriate 5% in water, sodium lauryl sulfate 5% in water, and thelike. In addition, materials such as anti-oxidants, humectants,viscosity stabilizers and the like also may be added if desired.

[0162] For enteral application, particularly suitable are tablets,dragees or capsules having talc and/or carbohydrate carrier binder orthe like, the carrier preferably being lactose and/or corn starch and/orpotato starch. A syrup, elixir or the like can be used wherein asweetened vehicle is employed. Sustained release compositions can beformulated including those wherein the active component is protectedwith differentially degradable coatings, e.g., by microencapsulation,multiple coatings, etc.

[0163] In addition to treatment of human subjects, the therapeuticmethods of the invention also will have significant veterinaryapplications, e.g. for treatment of livestock such as cattle, sheep,goats, cows, swine and the like; poultry such as chickens, ducks, geese,turkeys and the like; horses; and pets such as dogs and cats. Also, thecompounds of the invention may be used to treat non-animal subjects,such as plants.

[0164] It will be appreciated that the actual preferred amounts ofactive compounds used in a given therapy will vary according to thespecific compound being utilized, the particular compositionsformulated, the mode of application, the particular site ofadministration, etc. Optimal administration rates for a given protocolof administration can be readily ascertained by those skilled in the artusing conventional dosage determination tests conducted with regard tothe foregoing guidelines.

[0165] In general, compounds of the invention for treatment can beadministered to a subject in dosages used in prior minocyclinetherapies. See, for example, the Physicians' Desk Reference. Forexample, a suitable effective dose of one or more compounds of theinvention will be in the range of from 0.01 to 100 milligrams perkilogram of body weight of recipient per day, preferably in the range offrom 0.1 to 50 milligrams per kilogram body weight of recipient per day,more preferably in the range of 1 to 20 milligrams per kilogram bodyweight of recipient per day. The desired dose is suitably administeredonce daily, or several sub-doses, e.g. 2 to 5 sub-doses, areadministered at appropriate intervals through the day, or otherappropriate schedule.

[0166] It will also be understood that normal, conventionally knownprecautions will be taken regarding the administration of minocyclinesgenerally to ensure their efficacy under normal use circumstances.Especially when employed for therapeutic treatment of humans and animalsin vivo, the practitioner should take all sensible precautions to avoidconventionally known contradictions and toxic effects. Thus, theconventionally recognized adverse reactions of gastrointestinal distressand inflammations, the renal toxicity, hypersensitivity reactions,changes in blood, and impairment of absorption through aluminum,calcium, and magnesium ions should be duly considered in theconventional manner.

[0167] In one embodiment, the minocycline compounds of the invention donot include those described in U.S. patent application Ser. No.09/823,884, incorporated herein by reference.

[0168] Furthermore, the invention also pertains to the use of aminocycline compound of formula I or II, for the preparation of amedicament. The medicament may include a pharmaceutically acceptablecarrier and the minocycline compound is an effective amount, e.g., aneffective amount to treat a tetracycline responsive state.

EXEMPLIFICATION OF THE INVENTION

[0169] Compounds of the invention may be made as described below, withmodifications to the procedure below within the skill of those ofordinary skill in the art.

Example 1 Preparation of Minocycline Compounds of the Invention

[0170] Preparation of 9-Iodominocycline

[0171] To 200 ml of 97% methanesulfonic acid was slowly added, atambient temperature, portionwise [30 g;56.56 mM] ofminocycline-bis-hydrochloride salt. The dark yellow brown solution wasthen stirred at ambient temperature while [38 g;169.7 mM] ofN-iodosuccinimide was added, in six equal portions, over 3.0 hours time.The reaction was monitored via analytical LC, noting the disappearanceof the starting material.

[0172] The reaction was slowly quenched into 2 L of ice cold watercontaining [17.88 g;1134.1 mM] of sodium thiosulfate with rapidstirring. This quench was stirred for approximately 30 minutes atambient temperature. The aqueous layer was then extracted with 6×200 mlof ethyl acetate before the aqueous was poured onto [259.8 g;3.08 M] ofsodium hydrogen carbonate containing 300 ml of n-butanol. The phaseswere split and the aqueous extracted with 4×250 ml of n-butanol. Theorganic fractions were combined and washed with 3×250 ml of water andonce with 250 ml of saturated brine. The resulting organic phase wasreduced to dryness under reduced pressure. The residue was suspended inmethanol (˜600 ml) and anhydrous HCl gas was bubbled into this mixtureuntil solution occurred This solution was reduced to dryness underreduced pressure. The filtrates were reduced to dryness under reducedpressure. The resulting material was triturated with 300 ml of methylt-butyl ether and isolated via filtration. This material was redissolvedin 300 ml of methanol and treated with 0.5 g of wood carbon, filteredand filtrates reduced to dryness under reduced pressure. The materialwas again powdered under methyl t-butyl ether, isolated via suctionfiltration and washed with more ether, and finally hexanes. The materialwas vacuum dried to give 22.6 g of a light yellow brown powder.

[0173] General Procedure for Preparation of 9-Alkynyl MinocyclineCompounds 1 mmol 9-iodo minocycline, 50 mg tetrakis tripenylphosphinatopalladate, 12 mg palladium acetate, 32 mg copper (I) iodide aredissolved/suspended in 10 ml acetonitrile. 2 to 5 ml triethylamine and 3to 5 mmol alkynyl derivative is added. The reaction mixture isvigorously stirred between ambient temperature to 70° C. The reactiontime is 2-24 hours. When the reaction is completed the dark suspensionis filtered through a celite bed and concentrated. The crude product ispurified by prep HPLC. The combined fractions are concentrated and takenup in ˜1 ml methanol. ˜3 ml HCl saturated methanol is added, and theproduct is precipitated with ether.

[0174] General Procedure for Preparation of 9-Aryl Minocycline Compounds

[0175] 0.15 mmol of 9-iodominocycline, PdOAc (3.2 mg), 229 μl 2 M Na₂CO₃and 2 equivalents of phenyl boronic acid were dissolved/suspended in 10ml methanol. The reaction flask was purged with argon and the reactionrun for a minimum of four hours or until HPLC monitoring showsconsumption of starting material and/or the appearance of products. Thesuspension was filtered through celite, and subject to purification byprep HPLC on a divinylbenzene column.

[0176] Compound OU (9-(4-Trifluoromethoxyphenylureido)-MethylMinocycline)

[0177] To 3 mL of dimethylformamide was added 150 mg (0.25 mmol) of9-methyl aminominocyline trihydrochloride and 67 mL (0.50 mmol) oftriethylamine at 25° C. With stirring, 75 mL (0.50 mmol) of4-trifluoromethoxyphenylisocyanate was added and the resulting reactionmixture was stirred at 25° C. for two hours. The reaction was monitoredby analytical HPLC (4.6×50 mm reversed phase Luna C18 column, 5 minutelinear gradient 1-100% B buffer, A buffer was water with 0.1%trifluoroacetic acid, B buffer was acetonitrile with 0.1%trifluoroacetic acid). Upon completion, the reaction was quenched with 1mL of water and the pH adjusted to approximately 2.0 with concentratedHCl. The solution was filtered and the compound purified by preparativeHPLC. The yield of compound OU was 64 mg (37% yield). The purity ofCompound OU was 95% determined by LCMS (M+1=690).

[0178] Compound LA (9-(4′ Carboxy phenyl)Minocycline)

[0179] In a clean, dry reaction vessel, was placed 9-iodominocycline[500 mg; 0.762 mmoles] bis HCl salt, palladium (II) acetate [17.2 mg;0.076 mmoles] along with 10 ml of reagent grade methanol. The solutionwas immediately purged, with stirring, with a stream of argon gas forapproximately 5 minutes. The reaction vessel was brought to reflux andto it was sequentially added via syringe 2 M potassium carbonatesolution [1.91 ml; 3.81 mmoles], followed by a solution ofp-carboxyphenyl boronic acid [238.3 mg; 1.53 mmoles]in 5 ml of reagentDMF. Both of these solutions were previously degassed with argon gas forapproximately 5 minutes. The reaction was heated for 45 minutes, theprogress was monitored via reverse phase HPLC. The reaction wassuctioned filtered through a pad of diatomaceous earth and washed thepad with DMF. The filtrates were reduced to an oil under vacuum andresidue treated with t-butylmethyl ether. Crude material was purifiedvia reverse phase HPLC on DVB utilizing a gradient of water andmethanol/acetonitrile containing 1.0% trifluoroacetic acid. Productconfirmed by mass spectrum: found M+1 578.58; the structure corroboratedwith 1H NMR.

Example 2 In vitro Minimum Inhibitory Concentration (MIC) Assay

[0180] The following assay is used to determine the efficacy ofminocycline compounds against common bacteria. 2 mg of each compound isdissolved in 100 μl of DMSO. The solution is then added tocation-adjusted Mueller Hinton broth (CAMHB), which results in a finalcompound concentration of 200 μg per ml. The minocycline compoundsolutions are diluted to 50 μL volumes, with a test compoundconcentration of 0.098 μg/ml. Optical density (OD) determinations aremade from fresh log-phase broth cultures of the test strains. Dilutionsare made to achieve a final cell density of 1×10⁶ CFU/ml. At OD=1, celldensities for different genera should be approximately: E. coli 1 × 10⁹CFU/ml S. aureus 5 × 10⁸ CFU/ml Enterococcus sp. 2.5 × 10⁹ CFU/ml  

[0181] 50 μl of the cell suspensions are added to each well ofmicrotiter plates. The final cell density should be approximately 5×10⁵CFU/ml. These plates are incubated at 35° C. in an ambient air incubatorfor approximately 18 hr. The plates are read with a microplate readerand are visually inspected when necessary. The MIC is defined as thelowest concentration of the minocycline compound that inhibits growth.Compounds of the invention indicate good inhibition of growth.

[0182] In Table 1, compounds which were good inhibitors of growth of aparticular bacteria are indicated with *, compounds which were very goodinhibitors of a particular bacteria are indicated with **, and compoundswith were particularly good inhibitors of a particular bacteria areindicated with ***.

Equivalents

[0183] Those skilled in the art will recognize, or be able to ascertainusing no more than routine experimentation, numerous equivalents to thespecific procedures described herein. Such equivalents are considered tobe within the scope of the present invention and are covered by thefollowing claims. The contents of all references, patents, and patentapplications cited throughout this application are hereby incorporatedby reference. The appropriate components, processes, and methods ofthose patents, applications and other documents may be selected for thepresent invention and embodiments thereof. TABLE 1 ID STRUCTURE S aureusE hirae E coli KA

** ** * KB

*** *** ** KC

** ** * KD

** ** * KE

** *** * KF

*** *** * KH

** ** ** KI

** ** * KJ

** ** * KK

** ** ** KL

** ** * KM

** ** ** KN

*** ** ** KO

** ** ** KP

** ** * KQ

** ** ** KR

** ** ** KS

* * ** KT

* * * KU

** * *** KV

** ** ** KW

** ** * KX

** ** * KY

* * * KZ

** ** * LA

** ** * LB

** ** * LC

** ** * LD

** *** * LE

** ** * LF

* * * LG

** ** * LH

** ** * LI

** ** * LJ

** ** * LK

** * * LM

** ** * LN

** ** * LO

** ** * LP

** ** ** LQ

* * * LR

** ** ** LS

** ** ** LT

** ** ** LU

** ** * LV

* * * LW

** ** ** LX

** ** * LY

* * * LZ

* * * MA

** ** * MB

* * * MC

* * * MD

** ** ** ME

* ** * MF

* * * MG

** ** * MH

** ** ** MI

** ** * MK

* ** ** ML

** ** ** MM

** * ** MN

* * * MO

** ** * MP

** ** ** MQ

* * * MR

* ** * MS

*** *** ** MT

* * * MU

** ** * MV

** ** * MW

** ** * MX

** ** * MY

** ** * MZ

** ** ** NA

** ** * NB

* * * NC

* * * ND

* * * NE

*** *** *** NF

* * * NG

* * * NH

* * * NI

*** ** ** NJ

** ** ** NK

** ** * NL

** ** ** NM

** ** ** NO

** ** ** NP

** ** ** NQ

* * * NR

** ** ** NS

** ** ** NT

** ** ** NU

*** *** *** NV

* * * NW

* *** * NX

*** *** ** NY

* *** * NZ

** ** * OA

** ** * OB

** ** * OC

* * * OD

*** NT *** OE

* * * OF

* NT ** OG

** NT ** OH

*** NT *** OI

** NT * OJ

** NT * OK

** NT ** OL

* NT * OM

** NT * ON

** NT * OO

** NT ** OP

** NT ** OQ

** NT * OR

* NT * OS

* NT * OT

* NT * OU

** NT * OV

** NT ** OW

NT NT NT OX

NT NT NT OY

NT NT NT OZ

NT NT NT PA

NT NT NT PB

NT NT NT PC

NT NT NT PD

NT NT NT PE

NT NT NT PF

NT NT NT PG

NT NT NT PH

NT NT NT PI

NT NT NT PJ

NT NT NT PK

NT NT NT PL

NT NT NT PM

NT NT NT PN

NT NT NT PO

NT NT NT PP

NT NT NT PQ

NT NT NT PR

NT NT NT PS

NT NT NT PT

NT NT NT PU

NT NT NT PV

NT NT NT PW

NT NT NT PX

NT NT NT

1. A minocycline compound of formula I:

wherein: X is CHC(R¹³Y′Y), CR^(6′)R⁶, S, NR⁶,or O; R², R^(4′), R^(4″),R^(7′) and R^(7″) are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl,heterocyclic, heteroaromatic or a prodrug moiety; R⁴ is NR^(4′)R^(4″),alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen; R^(2′),R³, R¹⁰, R¹¹ and R¹² are each hydrogen or a pro-drug moiety; R⁵ ishydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl,heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy,or aryl carbonyloxy; R⁶ and R^(6′) are independently hydrogen,methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl,aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or anarylalkyl; R⁹ is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl,arylalkynyl, thionitroso, or —(CH₂)₀₋₃NR^(9c)C(═Z′)ZR^(9a); Z isCR^(9d)R^(9e), S, NR^(9b) or O; Z′ is NR^(9f), O or S; R^(9a), R^(9b),R^(9c), R^(9d), R^(9e) and R^(9f) are each independently hydrogen, acyl,alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromaticor a prodrug moiety; R⁸ is hydrogen, hydroxyl, halogen, thiol, alkyl,alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,alkylamino, or an arylalkyl; R¹³ is hydrogen, hydroxy, alkyl, alkenyl,alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, oran arylalkyl; Y′ and Y are each independently hydrogen, halogen,hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl,and pharmaceutically acceptable salts, esters and prodrugs thereof. 2.The minocycline compound of claim 1, wherein R⁴ is NR^(4′)R^(4″); X isCR⁶R^(6′); R², R^(2′), R⁵, R⁶, R^(6′), R⁸, R⁹, R¹⁰, R¹¹, and R¹² areeach hydrogen; and, R^(4′), R^(4″), R^(7′), and R^(7″)are each loweralkyl.
 3. The minocycline compound of claim 2, wherein R^(4′), R^(4″),R^(7″), and R^(7″) are each methyl.
 4. The minocycline compound of anyone of claims 1-3, wherein R⁹ is substituted or unsubstituted aryl. 5.The minocycline compound of claim 4, wherein R⁹ is substituted orunsubstituted phenyl.
 6. The minocycline compound of claim 5, wherein R⁹is unsubstituted phenyl.
 7. The minocycline compound of claim 5, whereinR⁹ is substituted with one or more substituents selected from the groupconsisting of halogen, hydroxyl, alkoxy, formyl, alkylcarbonyloxy,arylcarbonyloxy, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy,carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino,acylamino, amido, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.
 8. The minocyclinecompound of claim 7, wherein R⁹ is substituted with one or moresubstituents selected from the group consisting of carboxylate, alkyl,alkenyl, alkynyl, aryl, heterocyclic, cyano, amino, halogen, alkoxy,alkoxycarbonyl, amido, alkylcarbonyl, and nitro.
 9. The minocyclinecompound of claim 4, wherein R⁹ is substituted or unsubstitutedheteroaryl.
 10. The minocycline compound of claim 9, wherein saidheteroaryl is selected from the group consisting of furanyl, imidazolyl,benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl,benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl,methylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl,pyrazolyl, oxazolyl, isooxazolyl, naphthridinyl, thiazolyl,isothiazolyl, or deazapurinyl.
 11. The minocycline compound of claim 10,wherein said heteroaryl is thienyl or benzofuranyl.
 12. The minocyclinecompound of anyone of claims 1-3, wherein R⁹ is substituted orunsubstituted alkynyl.
 13. The minocycline compound of claim 12, whereinsaid substituted alkynyl group is substituted with a substituted orunsubstituted aryl group.
 14. The minocycline compound of claim 13,wherein said aryl group is substituted or unsubstituted phenyl.
 15. Theminocycline compound of claim 14, wherein said phenyl group issubstituted with a group selected from alkyl, alkenyl, halogen,hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl,alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate,aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido,imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano, azido,heterocyclyl, alkylaryl, aryl and heteroaryl.
 16. The minocyclinecompound of claim 13, wherein said aryl group is heteroaryl.
 17. Theminocycline compound of claim 12, wherein said alkynyl group issubstituted with alkyl, alkenyl, carboxylate, silyl, aralkyl, or aalkyloxycarbonyl group.
 18. The minocycline compound of claim 15,wherein said alkyl substituent is aminoalkyl.
 19. The minocyclinecompound of claim 18, wherein said aminoalkyl is substituted with aalkylsulfonamide group.
 20. The minocycline compound of claim 17,wherein said alkynyl group is substituted with a cycloalkenyl group. 21.The minocycline compound of claim 20, wherein said cycloalkenyl group iscyclopentenyl.
 22. The minocycline compound of any one of claims 1-3,wherein R⁹ is alkyl.
 23. The minocycline compound of claim 22, whereinsaid alkyl group is substituted with one or more substituents selectedfrom the group consisting of halogen, hydroxyl, alkoxy,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl,arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl,arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio,arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, alkenyl, cyano, azido, heterocyclyl, alkylaryl, aryland heteroaryl.
 24. The minocycline compound of claim 22, wherein saidalkyl group comprises a ring.
 25. The minocycline compound of claim 24,wherein said alkyl group is 2-cyclopentylethyl.
 26. The minocyclinecompound of anyone of claims 1-3, wherein R⁹ is —(CH₂)₀₋₃NR^(9c)C(═Z′)ZR^(9a).
 27. The minocycline compound of claim 26, whereinR⁹ is —NR^(9c)C(═Z′)ZR^(9a).
 28. The minocycline compound of claim 26,wherein R⁹ is —CH₂NR^(9c)C(═Z′)ZR^(9a)
 29. The minocycline compound ofclaim 27 or 28, wherein R^(9c) is hydrogen.
 30. The minocycline compoundof any one of claims 27-29, wherein Z′ is S.
 31. The minocyclinecompound of any one of claims 27-29, wherein Z′ is O.
 32. Theminocycline compound of any one of claims 27-31, wherein Z is NR^(9b).33. The minocycline compound of any one of claims 27-31, wherein Z is O.34. The minocycline compound of any one of claims 27-31, wherein Z is S.35. The minocycline compound of claim 32, wherein R^(9b) is hydrogen.36. The minocycline compound of anyone of claims 26-35, wherein R^(9a)is aryl.
 37. The minocycline compound of claim 36, wherein R^(9a) issubstituted or unsubstituted phenyl.
 38. The minocycline compound ofclaim 36, wherein said phenyl group is substituted with one or moresubstituents selected from the group consisting of halogen, hydroxyl,alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl,arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl,arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio,arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, acetyl, alkyl, cyano, azido, heterocyclyl,alkylaryl, aryl and heteroaryl.
 39. The minocycline compound of claim38, wherein said substituents selected from nitro, alkoxy, alkyl, acyl,halogen, or amino.
 40. The minocycline compound of claim 39, whereinsaid amino group is dialkylamino.
 41. The minocycline compound of claim39, wherein said alkoxy group is methoxy.
 42. The minocycline compoundof claim 39, wherein said alkoxy group is methylenedioxy.
 43. Theminocycline compound of claim 41, wherein said alkoxy group isperhalogenated.
 44. The minocycline compound of claim 43, wherein saidalkoxy group is perfluoromethoxy.
 45. The minocycline compound of claim39, wherein said alkyl group is methyl, ethyl, propyl, butyl, or pentyl.46. The minocycline compound of claim 39, wherein said halogen isfluorine, chlorine, bromine, or iodine.
 47. The minocycline compound ofclaim 36, wherein said phenyl group is unsubstituted phenyl,para-nitrophenyl, para-methoxy phenyl, para-perfluoromethoxy phenyl,para-acetyl phenyl, 3,5-methylenedioxyphenyl, 3,5-diperfluoromethylphenyl, para-bromo phenyl, para-chloro phenyl, or para-fluoro phenyl.48. The minocycline compound of claim 38, wherein R^(9a) isarylcarbonyl.
 49. The minocycline compound of claim 36, wherein R^(9a)is biaryl.
 50. The minocycline compound of claim 49, wherein R^(9a) isnaphthyl.
 51. The minocycline compound of any one of claims 26-35,wherein R^(9a) is substituted or unsubstituted alkyl.
 52. Theminocycline compound of claim 51, wherein R^(9a) is unsubstituted alkyl.53. The minocycline compound of claim 52, wherein R^(9a)is methyl,ethyl, propyl, butyl, or pentyl.
 54. The minocycline compound of claim51, wherein said alkyl is substituted with one or more substituentsselected from the group consisting of halogen, hydroxyl, alkoxy,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl,arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl,arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio,arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, alkenyl,heterocyclyl, alkylaryl, aryl and heteroaryl.
 55. The minocyclinecompound of any one of claims 26-35, wherein R^(9a) is substituted orunsubstituted alkenyl.
 56. The minocycline compound of claim 55, whereinR^(9a) is pent-1-enyl.
 57. The minocycline compound of claim 26, whereinZ′ is NH, Z is NH, and R^(9a) is alkyl.
 58. The minocycline compound ofany one of claims 1-3, wherein R⁹ is —N═S.
 59. The minocycline compoundof any one of claims 1-3, wherein R⁹ is aminoalkyl.
 60. The minocyclinecompound of claim 59, wherein said aminoalkyl is alkylaminoalkyl. 61.The minocycline compound of any one of claims 1-3, wherein R⁹ issubstituted or unsubstituted alkyl amino.
 62. The minocycline compoundof claim 61, wherein said alkyl amino is substituted with an aryl group.63. The minocycline compound of claim 62, wherein said aryl group issubstituted or unsubstituted phenyl.
 64. The minocycline compound ofclaim 63, wherein said substituted phenyl is methylenedioxyphenyl orpara-perfluoromethoxyphenyl.
 65. A minocycline compound or apharmaceutically acceptable salt thereof selected from the groupconsisting of:


66. A method for treating a tetracycline responsive state in a mammal,comprising administering to said subject a minocycline compound of claim1 or 65, such that said subject is treated.
 67. The method of claim 66,wherein said tetracycline responsive state is a bacterial infection. 68.The method of claim 67, wherein said bacterial infection is associatedwith E. coli.
 69. The method of claim 68, wherein said bacterialinfection is associated with S. aureus.
 70. The method of claim 68,wherein said bacterial infection is associated with E. faecalis.
 71. Themethod of claim 67, wherein said bacterial infection is resistant toother tetracycline antibiotics.
 72. The method of claim 66, wherein saidminocycline compound is administered with a pharmaceutically acceptablecarrier.
 73. The method of claim 66, wherein said subject is a human.74. A pharmaceutical composition comprising a therapeutically effectiveamount of a minocycline compound of claim 1 or 65 and a pharmaceuticallyacceptable carrier.
 75. A 9-substituted minocycline compound of theformula:

wherein: R^(4′), R^(4″), R^(7′), and R^(7″) are each alkyl; and R⁹ is apyridylethynyl group; an alkenylcarbamate group; a halo group; analkylacrylate group; a naphthyl group; a haloacetyl group; an alkylcarbamate group; a cyclopentyl or cyclopentenyl group; a benzofuranylgroup; a phenylpropiononeamino group; a tosylamino group; amethoxypyridyl group; an alkeneamino group; an N-t-butyl group; at-butylamide group; a hydroxybutylamino group; a hydroxypropylaminogroup; a phenyl group; a nitrophenyl group; a nitrophenylalkynyl group;an aminophenyl group; an alkoxyphenyl group; a halophenyl urea group; acyanophenyl group; a carboxyphenyl group; an acylphenyl group; analkylphenyl group; a halophenyl group; an alkoxyphenyl group; acarboxyalkylphenyl group; a phenylalkynyl group; an alkynyl group; analkylglycineethylester group; a styrene group; a thiophene group; and analkylaminophospho group; and pharmaceutically acceptable salts thereof.76. The 9-substituted minocycline compound of claim 74, wherein saidcompound is 9-isopropenyl carbamate minocycline,9-(2-pyridylethynyl)minocycline, 9-iodo minocycline, 9-butylacrylateminocycline, 9-naphthyl minocycline urea, 9-chloroacetyl minocycline,9-neopentyl minocycline carbamate, 9-cyclopentene minocycline,benzofuranyl minocycline, 9-(phenylpropiononeamino)minocycline,9-tosylamino minocycline, 9-(2-methoxy-3-pyridyl)minocycline,9-(N-2′-hydroxydecyl-9′-ene-amino)minocycline, N-t-butyl-minocycline,9-BOC-NH minocycline, 9-(N-2′-hydroxybutylamino)minocycline,9-(N-3-chloro,2-hydroxylpropylamino)minocycline, 9-phenyl minocycline,9-p-tolyl minocycline, 9-3′-nitrophenyl minocycline,9-(4-nitrophenylethynyl)minocycline, 9-(3-aminophenyl)minocycline,9-(4-chloro,2-trifluoromethylphenyl)minocycline urea,9-(p-methoxyphenyl)minocycline, 9-(4′-methoxyphenyl)minocycline,9-(3,4-methylenedioxyphenyl)minocycline, 9-(4′-cyanophenyl)minocycline,9-(4′-carboxyphenyl)minocycline, 9-(3-formylphenyl)minocycline,9-(4′-t-butylphenyl)minocycline, 9-(3-chlorophenyl)minocycline,9-(2′,4′-difluorophenyl)minocycline, 9-(3,4-difluorophenyl)minocycline,9-(4′-chlorophenyl)minocycline, 9-(3,4-dichlorophenyl)minocycline,9-(4′-trifluoromethylphenyl)minocycline, 9-(3-ethoxyphenyl)minocycline,9-(4-carboxymethylphenyl)minocycline, 9-(phenylethynyl)minocycline,9-(3-hydroxyphenylethynyl)minocycline, 9-(p-tolylethynyl)minocycline,9-(p-methoxyphenylethynyl)minocycline, 9-ethynyl minocycline,9-(p-fluoroethynyl)minocycline, 9-(trimethylsilylethynyl)minocycline,9-(propionyl)minocycline, 9-(cyclohexenylethynyl)minocycline,9-(1-cyclohexyl-1 -hydroxyethynyl)minocycline, 9-propylglycineethylesterminocycline HCl, or 9-methylglycineethylester minocycline, 9-styreneminocycline, 9-4′-fluorostyrene minocycline, 9-2-thiophene minocycline,9-(5′-chloro-2′-thiophene)minocycline,9-(p-methoxyphenylaminophospho)minocycline,9-(phenylaminophospho)minocycline, 9-(p-methoxyphenylaminophospho)minocycline, or 9-(phenylaminophospho)minocycline.
 77. A method fortreating a tetracycline responsive state in a subject, comprisingadministering to said subject a 9-substituted minocycline compound ofclaim 75 or 76, such that said tetracycline responsive state in saidsubject is treated.
 78. The method of claim 77, wherein saidtetracycline responsive state is a bacterial infection.
 79. The methodof claim 78, wherein said bacterial infection is associated with E.coli, S. aureus, or E. faecalis.
 80. The method of claim 78, whereinsaid bacterial infection is resistant to other tetracycline antibiotics.81. The method of claim 77, wherein said compound is administered with apharmaceutically acceptable carrier.
 82. A minocycline compound selectedfrom the group listed in Table
 1. 83. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim,75, 76, or 82 and a pharmaceutically acceptable carrier.